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Tissue factor cytoplasmic domain exacerbates post-infarct left ventricular remodeling via orchestrating cardiac inflammation and angiogenesis.

ABSTRACT: The coagulation protein tissue factor (TF) regulates inflammation and angiogenesis via its cytoplasmic domain in infection, cancer and diabetes. While TF is highly abundant in the heart and is implicated in cardiac pathology, the contribution of its cytoplasmic domain to post-infarct myocardial injury and adverse left ventricular (LV) remodeling remains unknown. Methods: Myocardial infarction was induced in wild-type mice or mice lacking the TF cytoplasmic domain (TF∆CT) by occlusion of the left anterior descending coronary artery. Heart function was monitored with echocardiography. Heart tissue was collected at different time-points for histological, molecular and flow cytometry analysis. Results: Compared with wild-type mice, TF∆CT had a higher survival rate during a 28-day follow-up after myocardial infarction. Among surviving mice, TF∆CT mice had better cardiac function and less LV remodeling than wild-type mice. The overall improvement of post-infarct cardiac performance in TF∆CT mice, as revealed by speckle-tracking strain analysis, was attributed to reduced myocardial deformation in the peri-infarct region. Histological analysis demonstrated that TF∆CT hearts had in the infarct area greater proliferation of myofibroblasts and better scar formation. Compared with wild-type hearts, infarcted TF∆CT hearts showed less infiltration of proinflammatory cells with concomitant lower expression of protease-activated receptor-1 (PAR1) - Rac1 axis. In particular, infarcted TF∆CT hearts displayed markedly lower ratios of inflammatory M1 macrophages and reparative M2 macrophages (M1/M2). In vitro experiment with primary macrophages demonstrated that deletion of the TF cytoplasmic domain inhibited macrophage polarization toward the M1 phenotype. Furthermore, infarcted TF∆CT hearts presented markedly higher peri-infarct vessel density associated with enhanced endothelial cell proliferation and higher expression of PAR2 and PAR2-associated pro-angiogenic pathway factors. Finally, the overall cardioprotective effects observed in TF∆CT mice could be abolished by subcutaneously infusing a cocktail of PAR1-activating peptide and PAR2-inhibiting peptide via osmotic minipumps. Conclusions: Our findings demonstrate that the TF cytoplasmic domain exacerbates post-infarct cardiac injury and adverse LV remodeling via differential regulation of inflammation and angiogenesis. Targeted inhibition of the TF cytoplasmic domain-mediated intracellular signaling may ameliorate post-infarct LV remodeling without perturbing coagulation.

SUBMITTER: Chong SY

PROVIDER: S-EPMC8490508 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Left ventricular systolic dysfunction (LVSD) occurs frequently after acute ST-segment elevation myocardial infarction (STEMI). The predisposing factors and underlying mechanism of post-infarct LVSD are not fully understood. The present study mainly investigated the correlation between glycaemic gap, a novel index of stress-induced hyperglycaemia (SIH), and post-infarct LVSD. METHODS:A total of 274 first STEMI patients were enrolled in this cross-sectional study. Transthoracic echocardiography was performed within 48 h after admission and at 6 months after discharge to obtain left ventricular ejection fraction (LVEF). The change in LVEF was calculated as LVEF at 6 months after discharge minus baseline LVEF. Additionally, post-infarct LVSD was defined as LVEF ? 50%. Most importantly, glycaemic gap was calculated as admission blood glucose (ABG) minus the estimated average glucose over the previous 3 months. RESULTS:In patients without diabetes mellitus (DM), multivariate linear regression analysis revealed that both glycaemic gap (Beta?=?- 1.214, 95% CI - 1.886 to - 0.541, p?<?0.001) and ABG (Beta?=?- 1.124, 95% CI - 1.795 to - 0.453, p?=?0.001) were associated with change in LVEF. In DM patients, only glycaemic gap was still associated with change in LVEF, although this association was not observed in univariate linear regression analysis. Regarding the association between SIH and post-infarct LVSD, multivariate logistic regression analysis revealed that both glycaemic gap (OR?=?1.490, 95% CI 1.043 to 2.129, p?=?0.028) and ABG (OR?=?1.600, 95% CI 1.148 to 2.229, p?=?0.005) were associated with an increased risk of having post-infarct LVSD in non-DM patients. However, after multivariate adjustment in DM patients, only glycaemic gap (OR?=?1.399, 95% CI 1.021 to 1.919, p?=?0.037) remained associated with an increased risk of having post-infarct LVSD. Furthermore, the predictive value of glycaemic gap for post-infarct LVSD was not inferior to ABG in non-DM patients (p?=?0.499), and only glycaemic gap, instead of ABG, could significantly predict post-infarct LVSD in DM patients (AUC?=?0.688, 95% CI 0.591 to 0.774, p?=?0.002). CONCLUSIONS:Glycaemic gap was strongly associated with a change in LVEF and an increased risk of having post-infarct LVSD in patients following STEMI. In STEMI patients with DM, glycaemic gap could provide more valuable information than ABG in identifying patients at high risk of developing post-infarct LVSD.

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Tissue factor cytoplasmic domain exacerbates post-infarct left ventricular remodeling via orchestrating cardiac inflammation and angiogenesis.

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